Key takeaways:
- Neurokinin receptor antagonists have transformed VMS care, with FDA approvals of fezolinetant and elinzanetant offering effective nonhormonal options for postmenopausal women.
- Elinzanetant demonstrated robust efficacy and rapid onset, reducing moderate to severe hot flashes by nearly 74% at 12 weeks and showing additional benefits for sleep with a favorable safety profile.
- Fezolinetant remains a foundational nonhormonal therapy, supported by diverse clinical trial data showing nearly 60% reductions in hot flash frequency and broad real-world use since its 2023 approval.
- Menopausal hormone therapy labeling is being reassessed, as the FDA removed boxed warnings in 2025 after reevaluating WHI data and changes in patient age, formulations, and routes of administration.
- Future nonhormonal therapies are emerging, including cendifensine, which targets the monoamine system and has shown large, early reductions in hot flash frequency and severity in phase 2 trials.
In 2025, major shifts to the landscape of non-hormonal therapies available for treating vasomotor symptoms (VMS) in postmenopausal women were reported, the most recent being the FDA approval of elinzanetant (Lynkuet; Bayer) in this population on October 24, 2025.1
Elinzanetant is a neurokinin receptor antagonist, a method of treatment which, according to JoAnn V. Pinkerton, MD, division director of midlife health at UVA Health, has begun to reshape the VMS landscape.2 Thermoregulatory instability during menopause has been linked to overactivity in certain hypothalamic neurons caused by declining estrogen levels.
Mechanism of action
These neurons are known as the kisspeptin, neurokinin B, dynorphin (KNDy) system, and by interrupting this process, neurokinin receptor antagonists can reduce the frequency of hot flashes without the use of estrogen. As a dual NK1/NK3 receptor antagonist, elinzanetant may also lead to mood and sleep benefits through substance P pathways.2
Alongside elinzanetant, fezolinetant (Veozah; Astellas Pharma) received FDA approval as a neurokinin receptor antagonist available for treating VMS in postmenopausal women on May 12, 2023.3 By targeting the neurons that cause hot flashes as a nonhormonal option, fezolinetant can provide symptom relief without increasing breast and uterus risks.
Reassessing the risks of menopausal hormone therapy
Risks associated with hormonal therapies have previously been reported to patients through boxed warnings on the products’ labeling.4 In the Women’s Health Initiative (WHI) trials, increased risks of stroke and breast cancer were reported in patients receiving menopausal hormonal therapy (MHT).
This data led to class-wide boxed warnings being added to MHT starting in 2003. However, the FDA noted that WHI participants had an increased older age vs the general population taking therapy for hot flash relief, increasing their baseline risks.4
Compared to the mean age of 51 years in patients starting MHT, dementia findings in the WHI were based on women aged 65 to 79 years. The primary version of hormone therapy has also changed since this data was published, from oral conjugated equine estrogens plus medroxyprogesterone acetate to versions with transdermal estradiol, which reduces venous thrombosis risk.4
Based on this information, the FDA announced actions to revise safety labelling for MHT on November 10, 2025. These changes included:4
- Removing warnings about cardiovascular disease, breast cancer, and dementia
- Removing most references to endometrial cancer
- Removing recommendations to use the lowest dose for the shortest duration
Currently, warnings about breast cancer risk remain for labelings outside of boxed warnings for systemic therapy. Further research is needed to understand the link between MHT and breast cancer.4
“It's important to note that we need more data to make up for the dearth of research in this domain and until we better understand the full impact of MHT on breast cancer risk, women with a personal history of breast cancer remain ineligible for MHT,” said Nora Lansen, MD, chief medical officer at Elektra Health.4
Clinical evidence supporting fezolinetant
During the period of boxed warnings for hormonal options, multiple nonhormonal treatments rose in the vasomotor symptom landscape. At the 2023 ACOG Annual Clinical & Scientific Meeting, Genevieve Neal-Perry, MD, PhD, professor at the University of North Carolina at Chapel Hill, presented data regarding the safety and efficacy of fezolinetant.3
The study presented included a wide diversity of patients, with 20% being non-caucasian and many identifying as Black. Obese patients were also included, despite often being excluded from hot flash-related research. Among this study population, a nearly 60% decrease in the frequency of hot flashes was reported among patients taking fezolinetant.3
According to Neal-Perry, this highlights an opportunity to improve patient quality of life and financial wealth, which data has indicated are both adversely impacted by VMS. Fezolinetant was approved in 2023, making it the first effective nonhormonal therapy to manage these symptoms and support patients impacted by hot flashes.3
Elinzanetant phase 3 data
More recently, elinzanetant was approved following positive phase 3 data from the OASIS program, which highlighted significant safety and efficacy from the medication.1 Positive outcomes included a -73.8% reduction in the frequency of moderate to severe VMS among patients taking elinzanetant between baseline and week 12, vs -47% in those taking placebo.
"It's a new option among other options for the treatment of vasomotor symptoms due to menopause—an option that has rapid onset, beneficial effects, very few side effects, and no significant adverse effects as seen with other therapies,” said James A. Simon, MD, CCD, MSCP, IF, FACOG, clinical professor of Obstetrics and Gynecology at the George Washington University.1
Alongside this outcome, a mean change in symptom severity of -1.2 was reported in elinzanetant patients, vs -0.8 in placebo patients. Additionally, sleep disturbances were measured using the Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form, with mean score reductions of -9.4 and -5.7, respectively, reported by week 12.1
While 70% of patients taking elinzanetant reported treatment-emergent adverse events, only 4.2% were serious, and none of these severe events were considered treatment-related. For those taking placebo, rates were 61.1% and 1.9%, respectively.1
Rapid onset and long-term efficacy
According to Pinkerton, these positive effects begin to appear within days, with sustained efficacy recorded 52 weeks through clinical trials. While longer-term safety data is ongoing, Pinkerton stated these early findings are encouraging.2
“For many years, hormone therapy was really the only highly effective therapy that we had, but now we have an understanding of how the pathogenesis of vasomotor symptoms are coming from the central role of these neurokinin receptors,” said Pinkerton.2
This highlights an alternative method to hormonal therapy, which was the only reliable option for hot flashes among postmenopausal women for many years. Currently, the OASIS-4 trial is evaluating the potential of elinzanetant for breast cancer survivors in endocrine therapy, providing vital treatment to this population.2
Comparing elinzanetant and fezolinetant
Fezolinetant and elinzanetant present with different risk and side effect profiles, and Neal-Perry has highlighted how this allows patients to choose the one preferred based on their individual health profile.5 For example, elinzanetant has been linked to increased drowsiness, but this outcome has not been reported from fezolinetant, making the former more beneficial in women with sleep problems.
Alongside health benefits, access may differ between the 2 methods, with fezolinetant’s earlier approval leading it to be included on more insurance formularies vs elinzanetant. Potential increases in liver enzymes have been reported in both medications, though protocols may differ.5
Real-world evidence has also emerged to highlight additional benefits of fezolinetant. This includes early data indicating increased efficacy from fezolinetant against hot flashes when compared with selective serotonin reuptake inhibitors. Additionally, a favorable safety profile has been reported alongside minimal liver concerns in practice.5
To further personalize symptom relief, Neal-Perry noted real-world studies are being conducted. Additional effects are being investigated, such as whether neurokinin receptor antagonists can modify long-term risks of cardiovascular disease, inflammation, and cognitive decline associated with severe, untreated hot flashes.5
“The reason this is so important is that it’s been many years since we’ve had anything new and novel on the market to treat hot flashes, and quite frankly, it has only been with these 2 drugs that we have a treatment that’s specific,” said Neal-Perry.5
Cendifensine and other future options
Looking ahead, research is ongoing for other nonhormonal vasomotor symptom therapies, such as cendifensine, which was discussed in an interview with Contemporary OB/GYN and Rebecca Dunsmoor-Su, MD, chief medical officer for Gennev.6 The efficacy of cendifensine across multiple doses was evaluated in a phase 2 clinical trial.
Clinically meaningful improvements were reported for all tested doses, with an 82% reduction in moderate to severe hot flashes reported by week 4 in women taking the lower dose. By week 12, this reduction increased to 92%.6
There were also significant reductions in symptom severity. By weeks 4 and 12, severity reductions of 42% and 59%, respectively, were reported in patients receiving lower doses. Greater effects were observed in patients taking higher doses, indicating the efficacy of cendifensine toward reducing both the frequency and severity of hot flashes.6
Dunsmoor-Su highlighted these findings as significant because of cendifensine’s novel mechanism of action. Compared to fezolinetant and elinzanetant, which target the KNDy system, cendifensine acts through the monoamine system, which allows for improvements in serotonin, norepinephrine, and dopamine signaling alongside KNDy modulation.6
Thanks to this broader mechanism, cendifensine can be used to manage symptoms that often coincide with hot flashes, such as mood changes and food cravings. Larger phase 3 trials will allow optimal dosing to be confirmed, alongside confirming effectiveness and further assessing safety.6
“After those larger trials are done, then that drug can go up to the FDA to look for approval for this indication, and possibly other indications if they get [a] good signal on those,” said Dunsmoor-Su.6
References
- Krewson C. FDA approves elinzanetant (Lynkuet) for vasomotor menopausal symptoms. Contemporary OB/GYN. October 24, 2025. Accessed October 29, 2025. https://www.contemporaryobgyn.net/view/fda-approves-elinzanetant-lynkuet-for-vasomotor-menopausal-symptoms
- Pinkerton JV, Liss J. Special Report: How neurokinin receptor antagonists are reshaping the VMS treatment landscape. Contemporary OB/GYN. October 27, 2025. Accessed October 30, 2025. https://www.contemporaryobgyn.net/view/special-report-how-neurokinin-receptor-antagonists-are-reshaping-the-vms-treatment-landscape
- Ebert M. 'It's about time,' fezolinetant approval and latest research showcased at annual meeting. May 19, 2023. Accessed October 30, 2025. https://www.contemporaryobgyn.net/view/-it-s-about-time-fezolinetant-approval-and-latest-research-showcased-at-annual-meeting
- Ebert M. FDA initiates removal of boxed warnings, requests updated labeling for menopausal hormone therapy. November 10, 2025. Accessed December 8, 2025. https://www.contemporaryobgyn.net/view/fda-initiates-removal-of-boxed-warnings-from-hormone-therapy-for-menopause
- Neal-Perry G. Genevieve Neal-Perry, MD, PhD, discusses new nonhormonal treatments for hot flashes. Contemporary OB/GYN. December 8, 2025. Accessed December 8, 2025. https://www.contemporaryobgyn.net/view/genevieve-neal-perry-md-phd-discusses-new-nonhormonal-treatments-for-hot-flashes
- Dunsmoor-Su R. Rebecca Dunsmoor-Su, MD, highlights reduced hot flashes from cendifensine. Contemporary OB/GYN. December 4, 2025. Accessed December 8, 2025. https://www.contemporaryobgyn.net/view/rebecca-dunsmoor-su-md-highlights-reduced-hot-flashes-from-cendifensine
